The regulation of cancer cell glutamine metabolism

We are grateful to Dorai, Pinto, and Cooper for their insightful Commentary on our manuscript ‘The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy’ (1,2). As summarized in the Commentary, glutaminase (GLS) catalyzes the first reaction of mitochondrial glutamine catabolism, generating glutamate and ammonia, and is overexpressed in a number of malignancies. Studies using small-molecule inhibitors or genetic approaches to suppress GLS have found that its activity can be important for cancer cell proliferation in vitro and for tumor growth in vivo. Indeed, the GLS inhibitor CB-839 is currently being evaluated in clinical trials for treatment of hematological cancers and triple-negative breast cancer (TNBC) (3,4). In our study, we found that c-Jun, which is up-regulated in TNBC as well as in a number of other human cancers, drives expression of the GLS gene and ultimately causes cancer cells to become dependent on the GLS reaction.